Dynamic interactions of the tumor suppressor protein p53 with a DNA fragment containing a p53-specific consensus sequence were directly observed on a single-molecule basis by time-lapse tapping mode atomic force microscopy (AFM) in liquid. Divalent cations were used to loosely attach both DNA and p53 to a mica surface so they could be imaged by time-lapse AFM while being sufficiently mobile to interact with each other. Various interactions of p53 with DNA were imaged in real-time, including dissociation/re-association, sliding and possibly direct binding to the specific sequence. Two modes of target recognition of p53 were detected: (a) direct binding, and (b) initial nonspecific binding with subsequent translocation by one-dimensional diffusion of the protein along the DNA to the specific site. These results give new insights to the motion of single biomolecules.